ABSTRACT

Context.— For the treatment of a single metastasis to the brain, surgical resection
combined with postoperative radiotherapy is more effective than treatment
with radiotherapy alone. However, the efficacy of postoperative radiotherapy
after complete surgical resection has not been established.

Objective.— To determine if postoperative radiotherapy resulted in improved neurologic
control of disease and increased survival.

Design.— Multicenter, randomized, parallel group trial.

Setting.— University-affiliated cancer treatment facilities.

Patients.— Ninety-five patients who had single metastases to the brain that were
treated with complete surgical resections (as verified by postoperative magnetic
resonance imaging) between September 1989 and November 1997 were entered into
the study.

Main Outcome Measures.— The primary end point was recurrence of tumor in the brain; secondary
end points were length of survival, cause of death, and preservation of ability
to function independently.

Results.— Recurrence of tumor anywhere in the brain was less frequent in the radiotherapy
group than in the observation group (9 [18%] of 49 vs 32 [70%] of 46; P<.001). Postoperative radiotherapy prevented brain
recurrence at the site of the original metastasis (5 [10%] of 49 vs 21 [46%]
of 46; P<.001) and at other sites in the brain
(7 [14%] of 49 vs 17 [37%] of 46; P <.01). Patients
in the radiotherapy group were less likely to die of neurologic causes than
patients in the observation group (6 [14%] of 43 who died vs 17 [44%] of 39; P =.003). There was no significant difference between the
2 groups in overall length of survival or the length of time that patients
remained functionally independent.

Conclusions.— Patients with cancer and single metastases to the brain who receive
treatment with surgical resection and postoperative radiotherapy have fewer
recurrences of cancer in the brain and are less likely to die of neurologic
causes than similar patients treated with surgical resection alone.

Figures in this Article

FOR PATIENTS with single metastases to the brain and limited systemic
disease, 2 randomized trials1,2
have shown that surgical resection combined with postoperative whole-brain
radiotherapy (WBRT) is superior to treatment with WBRT alone. (Although it
should be noted that 1 randomized trial3 failed
to show a benefit from surgery.) Postoperative radiotherapy was used in all
of the previous randomized trials assessing the efficacy of surgery in the
treatment of single brain metastases because it was felt to be effective both
in destroying any tumor left in the operative bed and in eliminating undetected
micrometastases elsewhere in the brain. However, the rationale for postoperative
WBRT is based on unproven assumptions. Given that most metastases are discrete
masses and do not infiltrate diffusely into the brain, it is possible that
metastases are capable of being totally removed by surgery. Also, improvements
in neuroimaging, especially contrast-enhanced, high-resolution magnetic resonance
imaging (MRI), may make it possible to detect small metastases and the residual
tumor and make the routine use of postoperative WBRT unnecessary.

The value of postoperative WBRT has not been tested in a randomized
trial; however, there have been 6 retrospective series4- 9
analyzed (Table 1). Because of
conflicting results, these studies have failed to determine the role, if
any, of postoperative radiotherapy. Therefore, we conducted a prospective
randomized trial comparing the effectiveness of surgery plus postoperative
radiotherapy with that of surgery alone to determine if postoperative WBRT
resulted in improved neurologic control of disease and increased survival.

METHODS

Eligibility of Patients

Patients at least 18 years old who had a tissue-proven diagnosis of
metastatic brain tumor obtained from a complete resection of a single brain
metastasis were eligible for the study. Patients were excluded if they had
brain metastases that had not been completely removed by surgery, evidence
of leptomeningeal metastases, a history of previous cranial radiotherapy,
a need for immediate treatment to prevent acute neurologic deterioration,
concomitant second malignancies, Karnofsky performance scores10
lower than 70%, or certain radiosensitive primary tumors (small-cell lung
cancer, germ-cell tumors, lymphoma, leukemia, and multiple myeloma).

Study Design

The study was a randomized trial with 2 treatment groups (Figure 1). The experimental protocol was approved by the institutional
review boards of the University of Kentucky, Lexington, and of the other
individual institutions that participated in the trial through the Southwest
Oncology Group, the Radiation Therapy Oncology Group, and the Brain Tumor
Cooperative Group. Written informed consent was obtained from each patient
before entry into the study.

Figure 1.—Randomization of patients into radiotherapy group
and observation group.

Before randomization, all patients had gadolinium-contrast MRI scan
of the head 2 to 5 days after surgery to rule out multiple lesions and to
confirm that the brain metastases had been completely resected. The pathologic
lesion from the surgical resection was reviewed at a central site to ensure
that patients had metastatic tumors. All patients also received an extent
of disease evaluation consisting of a chest x-ray film, hematologic and chemical
profiles, and other studies deemed appropriate for each patient's particular
primary tumor.

Prior to randomization, patients were stratified by (1) extent of disease
(brain metastasis only, brain metastasis plus primary site only, and brain
metastasis plus primary site plus at least 1 additional site) and (2) primary
tumor type (lung, breast, and other). Computer-generated random numbers at
a central site were then used to assign patients to 1 of 2 treatment groups.
The observation group received surgery only with no further treatment for
the brain metastasis. The radiation group received surgery plus postoperative
WBRT. At the time of randomization, all patients not already taking corticosteroids
began treatment with 4 mg of dexamethasone sodium phosphate every 6 hours
(or other corticosteroid in equivalent doses). In the observation group, corticosteroids
were tapered and use was discontinued within 2 weeks following surgery, when
possible.

For patients in the radiation group, radiotherapy was started within
28 days after surgery. Use of corticosteroids was continued without tapering
through the first 2 weeks of radiation therapy and then tapered and stopped,
if tolerated. The WBRT was given using lateral ports covering the brain and
meninges to the foramen magnum. Patients received 50.4 Gy of WBRT over 512 weeks (1.8 Gy×28 fractions) prescribed to the cranial midline.
This dose and fractionation scheme were chosen because the total dose was
large enough to be effective against micrometastases,11,12
and evidence from retrospective data13,14
suggested that low, daily fractionation schemes may result in fewer long-term
neuropsychological adverse effects.

In both treatment groups, MRI scans were repeated at 3-month intervals
for the first year following treatment and every 6 months thereafter. The
MRIs were reviewed at a central site. Patients also had MRI scans at any time
they developed symptoms suggesting neurologic progression or recurrence of
their brain metastases. If a recurrence was detected, further treatment was
given at the discretion of the patient's physicians and was not dictated by
the study.

Evaluation and Criteria for Response

To compare efficacy of treatments, we evaluated radiographic evidence
of recurrence of the brain metastasis, length of time to recurrence, length
of survival, cause of death, and changes in functional performance in the
2 treatment groups. Recurrence of brain metastases was determined by MRI scans,
and development of leptomeningeal metastases was verified by examination of
cerebrospinal fluid. A recurrence of the original brain metastasis was defined
as the reappearance of a metastasis in exactly the same site in the brain
as the first metastasis. The length of time to recurrence of the original
brain metastasis was calculated from the date of surgery for the metastasis
to the date that a recurrence was detected by MRI. A distant recurrence in
the brain was defined as the appearance of a new brain metastasis at a site
different from that of the original metastasis; leptomeningeal metastases
were also considered distant metastases. Length of survival was calculated
from the day of surgical removal of the brain metastasis to death or last
follow-up evaluation.

For all patients who died, an attempt was made to determine the cause
of death. Patients were considered to have died of neurologic causes if they
had stable systemic disease and progressive neurologic dysfunction. Patients
with severe neurologic disability who died of intercurrent illness were also
included among neurologic deaths, as were patients with both rapidly progressive
systemic disease and advancing neurologic dysfunction, because these patients
also represent brain treatment failures. The systemic cancer was considered
the only cause of death if, in the setting of neurologic improvement or stabilization,
patients developed fatal infections, hemorrhages, or failure of vital organ
systems other than the brain. Patients whose deaths could not be determined
to be either neurologic or systemic were classified as unknown.

The ability to function independently after treatment of the brain metastasis
was measured by the length of time Karnofsky scores10
remained at 70% or higher.

Statistical Analysis

To estimate the sample size needed, results from the 3 nonrandomized
retrospective studies, which were available at the start of our study (1989),
were used to derive estimates of overall brain recurrence rates (Table 2). To compare 2 recurrence rates
with a 2-tailed test (χ2) at the .05 α level having
an 80% power when one of the recurrence rates was 39% and the other was 73%,
a minimum of 40 patients per group were needed.

Survival curves were drawn using the Kaplan-Meier product limit method.15 When survival curves were based on neurologic causes
of death, deaths from other causes were treated as censored. When survival
curves were based on nonneurologic causes of death, deaths from neurologic
causes were treated as censored. The log-rank test was applied to compare
differences between 2 or more survival curves. To determine if censoring deaths
due to competing causes affected the comparison of survival curves, cause-specific,
survival-failure probability curves were also constructed and compared.16 Multivariate analyses were based on a Cox regression
model17 in which a stepwise proportional hazards
analysis identified the best subset of covariates associated with each time-dependent
end point. The covariates examined in all cases were the treatment group,
age, sex, location of brain metastasis, primary tumor type, extent of disease,
initial Karnofsky score, and the length of time between diagnosis of primary
and development of brain metastasis. Additional covariates were examined as
appropriate and are noted in the "Results" section. The χ2
test was used to determine the relationship between 2 categorical variables,
and the Fisher exact test was used when small cell sizes were encountered
in 2 × 2 contingency tables. A 2-tailed t test
was used to compare the means of continuous variables between the 2 treatment
groups.

RESULTS

Enrollment, Patient Flow, and Characteristics of Patients

The study opened in September 1989 at the University of Kentucky. During
the years 1992 to 1994, the Southwest Oncology Group, Radiation Therapy Oncology
Group, and the Brain Tumor Cooperative Group also contributed patients to
the trial. The last patient entered the study in March 1997, and the last
follow-up for all patients was November 1, 1997.

A total of 146 patients were eligible for the study and 95 patients,
46 in the observation group and 49 in the radiation group, actually entered
the study (Figure 1). The reasons
why 51 eligible patients were not randomized included patient refusal and
physician preference for a specific treatment. The study patients' baseline
characteristics are shown in Table 3.
As of November 1, 1997, 82 of the 95 patients had died (39/46 [85%] in the
observation group and 43/49 [88%] in the radiation group), and the median
follow-up time on living patients was 132 weeks in the observation group
and 127 weeks in the radiation group (P=.77). The
overall median follow-up times were 43 weeks in the observation group and
48 weeks in the radiation group (P=.58). No patients
were lost to follow-up.

There were 3 protocol violations involving radiotherapy. Two patients
who were randomized to receive radiotherapy were given nonprotocol doses (30
Gy and 36 Gy instead of 50.4 Gy). One patient who was randomized to receive
no radiotherapy was instead given WBRT (30 Gy). These patients were included
in the data analysis and, in accordance with an intention-to-treat analysis,
were analyzed along with the treatment group they were originally assigned
to by the initial randomization procedure.

Recurrence of Brain Metastases

The addition of postoperative radiotherapy resulted in substantially
better control of tumor in the brain than did treatment with surgery alone.
As shown in Table 4, the recurrence
rate of tumor anywhere in the brain was significantly less (P<.001) in the radiation group (9/49 [18%]) than in the observation
group (32/46 [70%]). The time to any brain recurrence (Figure 2) was also significantly longer in the radiation group.
Multivariate analysis showed that only postoperative radiotherapy lessened
the risk of brain recurrence (P<.001).

Figure 2.—The length of time to recurrence of tumor anywhere
in the brain was significantly (P<.001) longer
in patients in the radiotherapy group (white squares) than in the observation
group (black circles), median 220 weeks vs 26 weeks (relative risk of any
brain recurrence, 4.94; 95% confidence interval, 2.36-10.35). Tick marks indicate
patients (living or dead) in whom brain recurrences did not develop.

Postoperative radiotherapy reduced the recurrence rate at the original
site of operative treatment. Recurrence of the original brain metastases (independent
of distant brain metastases or leptomeningeal metastases) was significantly
lower (P<.001) in the radiation group (5/49 [10%])
than in the observation group (21/46 [46%]). In addition, time from treatment
to the development of recurrence of the original brain metastases (Figure 3) was significantly longer in the
radiation group (>52 weeks) than in the observation group (median, 27 weeks).
Multivariate analysis indicated that only postoperative radiotherapy of the
brain metastasis (P<.001) reduced the risk of
developing recurrence of the original brain metastases.

Figure 3.—The length of time from treatment to the development
of recurrence of the original brain metastases was significantly (P<.001) longer in patients in the radiation group (white squares)
than in the observation group (black circles), more than 50 weeks vs median
27 weeks (relative risk of original recurrence, 6.03; 95% confidence interval,
2.48-14.65). Recurrence of the original brain metastasis was defined as the
reappearance of a metastasis in the exact site in the brain as the first brain
metastasis. Tick marks indicate patients (living or dead) who did not develop
recurrences of the original metastasis.

Postoperative radiotherapy also prevented the subsequent development
of brain metastases at sites other than that of the original metastasis (distant
metastases). The occurrence of distant brain metastases or leptomeningeal
metastases (independent of recurrence of the original brain metastases) was
significantly less (P<.01) in the radiation group
(7/49 [14%]) than in the observation group (17/46 [37%]). Radiation significantly
delayed the development of distant brain metastases (Figure 4). Multivariate analysis showed that postoperative radiotherapy
(P=.02) and female sex (P=.04)
were associated with lower rates of recurrence of distant brain metastases.

Figure 4.—The length of time to recurrence of distant brain
metastasis was significantly (P=.04) longer in the
49 patients in the radiation group (220 weeks) (white squares) than in the
46 patients in the observation group (53 weeks) (black circles) (relative
risk of distant brain recurrence, 2.77; 95% confidence interval, 1.16-6.59).
Recurrence of distant brain metastasis was defined as the appearance of a
new metastasis at a site in the brain different from the site of the original
brain metastasis. Tick marks indicate patients (living or dead) who did not
develop distant brain metastases.

Survival

Overall Survival.— The survival times were not significantly different between the 2 groups.
The median length of survival in the 49 patients in the radiation group was
48 weeks vs 43 weeks in the 46 patients in the observation group (P=.39; relative risk [RR] of death, 0.91; 95% confidence interval [CI],
0.59-1.40). Multivariate analysis showed that the time between the diagnosis
of the primary tumor and the development of the brain metastasis was associated
with increased survival (P<.003).

Death Due to Neurologic Causes.— Postoperative radiotherapy prevented death due to neurologic causes.
Of all patients who died, 6 (14%) of 43 in the radiation group and 17 (44%)
of 39 in the observation group died neurologic deaths (P=.003). Radiotherapy also delayed death due to neurologic causes.
When the length of time to death due to neurologic causes in the 2 groups
was compared, there was a significant difference between the survival curves
(Figure 5). Construction of cause-specific
failure probabilities16 did not alter this
conclusion. Multivariate analysis demonstrated that WBRT was positively correlated
with increased neurologic survival (P<.009).

Figure 5.—When only deaths due to neurologic causes were used
as endpoints and data on patients who died from nonneurologic causes were
censored, there was a significant (P=.03) difference
between the 2 treatment groups. The radiation group (white squares) had a
median survival of more than 115 weeks, and the observation group (black circles)
had a median survival of 81 weeks (relative risk of death from neurologic
causes, 2.62; 95% confidence interval, 1.03-6.64). Length of survival was
measured from the beginning of treatment for the original brain metastasis.
Tick marks indicate patients who did not die of neurologic causes or the last
follow-up evaluation in living patients.

Death Due to Systemic Causes.— Patients in the radiation group were more likely to die of their systemic
cancer than as a result of neurologic progression. Of all patients who died,
36 (84%) of 43 in the radiation group and 18 (46%) of 39 in the observation
group died systemic deaths (P<.001). For unknown
reasons, patients in the observation group who did not die of neurologic causes
appeared to live longer than similar patients in the radiation group. When
survival was compared using death due to systemic causes as the only survival
end point (systemic death), there was a significant difference between the
2 treatment groups. The median length of systemic survival was 48 weeks in
the radiation group and 88 weeks in the observation group (P=.005; RR, 0.45; 95% CI, 0.26-0.79). Construction of cause-specific
failure probabilities16 did not alter this
conclusion.

Ability to Function Independently

There was no difference between the 2 groups in how long patients maintained
functional independence. The median length of time their Karnofsky scores
remained 70% or more after treatment of the original brain metastasis was
37 weeks in the radiation group and 35 weeks in the observation group (P=.61; RR, 0.84; 95% CI, 0.61-1.17).

COMMENT

This prospective, randomized trial shows that postoperative radiotherapy
given after a complete surgical resection of a single brain metastasis results
in substantially better control of disease in the brain and a reduction in
the number of deaths due to neurologic causes. We infer from these results
that radiotherapy was successful at eradicating microscopic metastases that
were undetected at the time of treatment.

The goal of treatment of brain metastasis is to eliminate the metastasis
and prevent recurrence of tumor in the brain. Metastases can recur after treatment
in 2 ways: (1) there can be recurrence at the original site in the brain or
(2) new metastasis at a brain site other than the original one (distant metastasis).
The reasons for the 2 types of failure are different. Recurrence at the original
site in the brain is almost always due to failure of the initial treatment
to completely destroy the metastasis. Our results show that surgery alone
does not always eliminate microscopic disease in the operative bed and that
postoperative MRI is not reliable for detecting the presence of residual tumor
after a "complete" resection. Forty-six percent of patients treated with surgery
alone had recurrence at the operative site, but postoperative radiotherapy
reduced that recurrence rate to 10%.

Failures at distant sites in the brain may result from either new metastases
spreading to the brain after treatment for the original brain tumor has been
completed (reseeding) or from the presence of additional (but undetected)
brain metastases that were present at the time of treatment of the original
brain metastasis. Postoperative WBRT reduced distant brain recurrences. The
implication from this is that most of the micrometastases at distant sites
were already present in the brain at the time that radiotherapy was given.
Radiotherapy would not have had an effect on metastases that were reseeded
to the brain after completion of treatment, and there is no evidence that
irradiated brain is a less "fertile soil" for subsequent metastases. Therefore,
although it is possible that a few recurrences were caused by reseeding, the
major mechanism of metastasis to the brain appears to be a single event consisting
of a shower of tumor emboli that become lodged at multiple sites in the brain.

An important corollary in the finding of undetected distant brain metastases
is that the number of genuine single metastases must be smaller than was previously
suspected. Studies18,19 using
computed tomographic scan data suggested that brain metastases were single
in slightly less than 50% of cases. However, more recent investigations20- 23 with
contrast-enhanced MRI have indicated that the percentage of single metastases
detected is only one third to one fourth of patients with cerebral metastases.
Our study shows that in more than one third (37%) of patients with only single
metastases detected by MRI, additional distant metastases were present. This
means that, overall, no more than 10% to 20% of patients with brain metastases
have true single metastases.

Despite the reduction in brain recurrence rates and neurologic deaths,
postoperative radiotherapy did not result in increased actuarial survival
or improve the length of time patients were able to function independently.
However, overall survival is determined by death due to both neurologic and
nonneurologic causes and is, therefore, not a direct measure of the success
of treatment for brain metastases. Patients in the radiotherapy group were
more likely to die of systemic than neurologic causes, and so systemic factors
were the major determinant of their length of survival. The absence of difference
in overall survival times between the 2 treatment groups was a result of the
lack of satisfactory treatment for the systemic cancers and not due to a failure
of postoperative radiotherapy to control disease in the brain.

Postoperative radiotherapy significantly prevented and delayed death
due to neurologic causes, which is all that can be expected of a treatment
directed solely at brain disease. The reduction in neurologic death was not
present in patients who did not receive radiotherapy in the immediate postoperative
period but were instead given WBRT only at recurrence. Neurologic death involves
the inexorable loss of mental and physical abilities and is the most difficult
type of death for patients and their families to deal with. The prevention
of a significant number of neurologic deaths is justification for the routine
use of postoperative radiotherapy.

Figure 2.—The length of time to recurrence of tumor anywhere
in the brain was significantly (P<.001) longer
in patients in the radiotherapy group (white squares) than in the observation
group (black circles), median 220 weeks vs 26 weeks (relative risk of any
brain recurrence, 4.94; 95% confidence interval, 2.36-10.35). Tick marks indicate
patients (living or dead) in whom brain recurrences did not develop.

Figure 3.—The length of time from treatment to the development
of recurrence of the original brain metastases was significantly (P<.001) longer in patients in the radiation group (white squares)
than in the observation group (black circles), more than 50 weeks vs median
27 weeks (relative risk of original recurrence, 6.03; 95% confidence interval,
2.48-14.65). Recurrence of the original brain metastasis was defined as the
reappearance of a metastasis in the exact site in the brain as the first brain
metastasis. Tick marks indicate patients (living or dead) who did not develop
recurrences of the original metastasis.

Figure 4.—The length of time to recurrence of distant brain
metastasis was significantly (P=.04) longer in the
49 patients in the radiation group (220 weeks) (white squares) than in the
46 patients in the observation group (53 weeks) (black circles) (relative
risk of distant brain recurrence, 2.77; 95% confidence interval, 1.16-6.59).
Recurrence of distant brain metastasis was defined as the appearance of a
new metastasis at a site in the brain different from the site of the original
brain metastasis. Tick marks indicate patients (living or dead) who did not
develop distant brain metastases.

Figure 5.—When only deaths due to neurologic causes were used
as endpoints and data on patients who died from nonneurologic causes were
censored, there was a significant (P=.03) difference
between the 2 treatment groups. The radiation group (white squares) had a
median survival of more than 115 weeks, and the observation group (black circles)
had a median survival of 81 weeks (relative risk of death from neurologic
causes, 2.62; 95% confidence interval, 1.03-6.64). Length of survival was
measured from the beginning of treatment for the original brain metastasis.
Tick marks indicate patients who did not die of neurologic causes or the last
follow-up evaluation in living patients.

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